Tardive Dyskinesia (TD) is a neurological syndrome consisting of spontaneous and largely uncontrollable oral or facial movements (such as chewing, swallowing, lip smacking and tongue protrusion) and head/neck movements. Choreiform movements of the fingers and other extremities are also commonly observed (McDowell et al., Clinical Neurology, Chapter 38, 1988; Lohr et al., Psychiatry, Chapter 70, 1989).
The condition is an undesirable side effect associated with long-term or high dose therapy with neuroleptic drugs. The condition appears after several months or years of neuroleptic therapy and persists after discontinuation of the drug or drugs. Symptoms may persist indefinitely, but in some cases slow remission is observed over months or years. In general, the likelihood of remission is lower with longer exposure to neuroleptics and with increasing age of the patient (McDowell et al., Clinical Biology, Chapter 38, 1988).
Estimates of the incidence of TD vary from about 10% to over 40% of the patients exposed to neuroleptic drugs for one year or longer. All types of neuroleptics seem to be associated with the syndrome, as well as antiemetic agents with dopamine receptor blocking actions (Wiholm et al., British Medical Journal, Vol. 288, pp. 545-547, 1984). Older patients appear to be at somewhat higher risk than younger patients (Tepper et al., Journal of Clinical Psychiatry, Vol. 40, pp. 508-516, 1979; Baldessarini, Journal of Clinical Psychiatry, Vol. 46, pp. 8-13, 1985).
The exact biochemical basis of the syndrome is not well understood. The prevailing opinion is that TD symptoms are largely, but not entirely, explained as manifestations of overactive central nervous system (CNS) dopaminergic systems. Dopamine receptor supersensitivity resulting from chronic treatment with dopamine receptor blockers is cited as a plausible cause of the apparent hyperdopaminergic state (Lohr et al., Psychiatry, Chapter 70, 1989). Dopaminergic hyperactivity could also result from enhanced synthesis and/or storage of dopamine as an adaptation to chronic presynaptic dopamine receptor blockade (Baldessarini et al. Annual Review of Neuroscience, Vol. 3, pp. 23-41, 1980).
The pharmacological profile of TD indicates that agents which tend to directly or indirectly inhibit CNS dopaminergic systems generally tend to relieve TD symptoms, while compounds which enhance dopaminergic transmission exacerbate the symptoms (Baldessarini et al. Annual Review of Neuroscience, Vol. 3, pp. 23-41, 1980). In particular, low doses of apomorphine, bromocriptine and amine depleting agents such as reserpine tend to be helpful (Fahn. Clinical Neuropharmacology, Vol. 6, pp. 151-158, 1983; Thorner et al., Bromocriptine: A Clinical and Pharmacological Review, Raven Press, New York, pp. 139-140, 1980). However, such compounds often have toxic or other undesirable side effects and frequently have a narrow and variable effective dose range which makes prolonged use difficult or impractical.
There are many obstacles to developing treatments which require the delivery of a drug to an active site in the body. Ingestion of a drug often is not possible because many drugs will not survive the environment of the stomach. Thus, easy and safe self administration of many drugs is not available. A drug, of course, can be injected directly into the blood stream of a patient. However, frequent injections at great inconvenience to a patient may be necessary because some drugs do not survive for very long in the bloodstream. The inability of a drug to survive in the bloodstream can be overcome in certain instances by increasing the dosage o by increasing the frequency of administration. However, the dosage can result in undesirable side effects and increasing the frequency of administration only adds inconvenience.
The delivery of a neuroactive drug to the central nervous system (CNS) via the bloodstream involves an extraordinary obstacle; the drug must be capable of crossing the blood brain barrier. The blood brain barrier may loosely be regarded as a biological exclusion barrier involving both passive and active transport, which barrier controls the exchange of materials between the plasma and the central nervous system. Many drug substances are unable to pass through this barrier in efficacious amounts or at all.